Jing Li, Xiaoxiao Wang, Liya Tu, Yufeng Chen
Ovarian cancer (OC) exhibits the highest mortality rate among gynecological cancers, and the development of chemotherapy resistance serves as the primary cause of patient recurrence and death. Natural products hold promise in reversing cisplatin (DDP) resistance. Trigonelline is a natural alkaloid possessing anti-tumor activity; however, it remains uncertain whether it can reverse DDP resistance in OC. In this study, DDP-resistant OC cell lines SKOV-3/DDP and A2780/DDP were successfully established. Cells were treated with non-toxic concentration of trigonelline in combination with DDP, and the molecular mechanism was investigated through the overexpression of Nrf2. Cell viability was detected to assess the sensitivity of the cells to DDP. Mitochondrial damage was evaluated by observing mitochondrial morphology, measuring mitochondrial membrane potential, ATP production, and ROS. Ferroptosis was assessed by detecting the levels of lipid peroxidation, MDA, SOD, Fe2+, and GSH/GSSG ratio in the cells. Additionally, the expression levels of ferroptosis-related proteins, namely Nrf2, HO-1, GPX4, and SLC7A11, were also detected. The results indicated that the utilization of low-concentration trigonelline exerted no toxic influence on OC drug-resistant cells, and instead potentiated the cytotoxicity of DDP against these cells. Furthermore, in comparison with the treatment using DDP alone, the combined treatment of trigonelline and DDP induced more severe mitochondrial damage and ferroptosis in drug-resistant cells. This led to the accumulation of ROS, notable increases in lipid peroxidation, MDA, and Fe2+ levels within the cells, while decreasing SOD activity and the ratio of GSH/GSSG, and down-regulating the expression of Nrf2, HO-1, GPX4, and SLC7A11 proteins. Nevertheless, the overexpression of Nrf2 reversed the combined effect of trigonelline and DDP. These results indicate that trigonelline reverses DDP resistance in OC cells by promoting ferroptosis via the regulation of the Nrf2/GPX4 signaling pathway.